reasonattlm

It starts with the death of companion animals. Not when you are young and comparatively resilient, but later in adult life when you are personally responsible for all of the decisions and costs, the management of a slow and painful decline. The futile delaying actions, the ugly realizations, the fading away, the lost capacity, the indignities and the pain, and all in an individual fully capable of feeling, but who lacks the ability to comprehend what is happening, or to help resist it. One slowly realizes that this is just a practice run for what will happen to everyone you know, later, and then to you. Ultimately it comes to euthanasia, and one sits there looking down at an animal who is a shadow of his or her previous self, second guessing oneself on degree of suffering, degree of spark and verve remaining. It is rarely a clear-cut choice, as in most companion animals the body fails before the mind. When it is clear, and your companion is dying in front of you, you will rush, and later chew it over for a long time afterwards; did you wait too long, could you have done better?

At some point you will ask yourself: why am I trying to maximize this life span? Why am I playing at balancing capacity against suffering? Why have I not just drawn an end to it? Why does it matter if a dog, a cat, another animal exists until tomorrow? Next year the animal will be gone without trace. In ten thousand years, it is most likely that you will be gone without trace. In a billion years, nothing recognizable will remain of the present state of humanity, regardless of whether there is continuation of intelligence or not. The great span of time before and after cares nothing for a dying companion animal. There is no meaning beyond whatever meaning you give to any of this, and there is a very thin line between that and the belief that there is no meaning at all, the belief that there is no point. If the animal you lived with will be gone, what was the point of it all? If you will be gone, why are you so fixated on being alive now, or tomorrow, or some arbitrary length of time from now?

It starts with companion animals, and it gnaws at you. The first of the cats and dogs you live with as the responsible party, the thinking party, the one motivated to find some meaning in it all, arrive and age to death between your twenties and your forties. That is traumatic at the end, but you find it was only practice, because by the end of that span of time, the first of the people closest to you start to die, in accidents and in the earlier manifestations of age-related disease. The death by aging of companion animals teaches you grief and the search for rationales - meaningless or otherwise - and you will go on to apply those lessons. To your parents, to mentors, to all of those a generation older who suddenly crumple with age, withering into a hospital or last years in a nursing facility. You are drawn into the sorry details of the pain and the futile attempts to hold on for the ones closest to you, a responsible party again. You are left thinking: why all this suffering? Why do we do this? What does it matter that we are alive? The span of a billion years ahead looms large, made stark and empty by the absence of those dying now, no matter how bustling it might in fact prove to be.

Grief and exposure to the slow collapse of aging in others: these are toxins. These are forms of damage. They eat at you. They diminish you, diminish your willingness to engage, to be alive, to go on. I think that this burden, as much as the physical degeneration of age, is why near all people are accepting of an end. The tiredness is in the mind, the weight of unwanted experiences of death by aging and what those experiences have come to mean to the individual. Human nature just doesn't work well under this load. It becomes easy to flip the switch in your view of the world: on the one side there is earnest work to end future suffering by building incrementally better medical technology, while on the other side lies some form of agreement with those who say that sadness and suffering can be cured by ending all life upon this world. Oh, you might recoil from it put so bluntly, but if you accept that existence doesn't matter, then the gentle, kind, persuasive ending of all entities who suffer or might suffer lies at the logical end of that road. It is just a matter of how far along you are today in your considerations of euthanasia and pain. This is the fall into nihilism, driven by the urge to flee from suffering, and the conviction that your own assemblies of meaning are weak and empty in the face of the grief that is past, and the grief that you know lies ahead.

Not all of the costs of the present human condition are visible as lines upon the face.

Links between early life adversity and later pace of aging and risk of age-related disease may be mediated by cytomegalovirus exposure.

https://doi.org/10.3389/fimmu.2017.01263

"The paper here finds that persistent cytomegalovirus infection is likely the mediating mechanism linking early life stress and later increased risk of age-related disease, acting through accelerated immune system dysfunction. This implies that the early stress may or may not be all that important, as - for whatever reason - the groups selected as examples of stress in early life are also more likely to be infected. That might be the short-term detrimental effects of stress on immune function, or it could be a matter of being in close contact with more distinct groups of people during childhood, as is the case for the adopted individuals in the study here. Cytomegalovirus is a persistent herpesvirus that the immune system cannot effectively clear from the body. Near everyone becomes infected at some point in life, and extensive evidence links this infection with immune system dysfunction. Increasing numbers of immune cells become dedicated to uselessly fighting cytomegalovirus, and ever fewer are left for everything else the immune system must accomplish. Other than this long-term corrosion, cytomegalovirus doesn't cause obvious symptoms in the vast majority of people - few notice the initial infection."

This is also compatible as a mechanism to explain greater disease risk in descendants, since growing up in an infected household presumably raises the risk of early infection with cytomegalovirus.

Control over your own end of life decisions is a right that is routinely denied in most of the world. It is a sad state of affairs. Similarly for medicine, and the right to choose your own medication and medical procedures.

Cryopreservation is a time-sensitive operation, and in practice akin to a surgical operation in the tools and people required. It runs best with preparation and forewarning, and as soon as possible after death. The primary cause of poor preservation and increased cost is the delay and rush forced on people because planned euthanasia is illegal in most jurisdictions, and as a result the providers are forced into a standby/emergency response model of operations.

Cryopreservation should be a form of euthanasia for best effect, for the lowest level of cell and tissue damage, and for the best odds of future restoration.

There will be many more people doing this sort of thing in the years ahead.

The main reason not to do it now for those genetic alterations known to exist in humans and have beneficial efforts, or to address genetic disease, would be that presently available approaches do not have reliable, high degrees of transfection. The cell coverage is low.

That is being solved. The work on gene therapy for muscular dystrophy is one line of research to watch as a marker of progress on this front.

As soon as reliable, high-enough levels of transfection are a reality, there will be a lot of unofficial gene therapy going on. The FDA and other regulators impose enormous cost and delay, as well as removing the agency of patients and those who desire enhancement rather than therapy. They will be bypassed, just as they were bypassed for stem cell therapies.

Also:

ANGPTL4: http://www.tum.de/en/about-tum/news/press-releases/short/art...

ASGR1: http://healthsciences.ku.dk/news/new-2016/mutation-protects-...

Growth hormone receptor: http://www.nbcnews.com/health/aging/little-people-ecuador-la...

And of course there are human loss of function myostatin mutants, but I can never find the articles I recall reading years back on some of the few known individuals.

Publicity materials (which, for a change, are actually useful and helpful): https://news.northwestern.edu/stories/2017/november/amish-li...

Paper: https://doi.org/10.1126/sciadv.aao1617

Researchers have found a noteworthy effect on longevity in a small study population that includes the only known individuals with a loss of function mutation in plasminogen activator inhibitor-1 (PAI-1). Individuals with the mutation live seven years longer on average than near relatives without it. Repeating the study with larger groups of people obviously isn't a practical option in the case of rare mutations - we're stuck with the family trees that the research community is fortunate enough to identify - but one nonetheless has to wish for more individuals, in order to obtain a more reliable confirmation, when an effect of this size is reported. It means taking a step back to revisit questions we've asked ourselves about the odds of finding significant longevity-enhancing mutations in our species, based upon the absence of results for the past twenty years of searching.

This is also a finding that can and probably should be taken as support for current work on elimination of senescent cells as a potential rejuvenation therapy. PAI-1 isn't a gene pulled from thin air in this context. It is well studied for its influence on aging, and appears to be one of the driving regulators of the harmful effects of cellular senescence. Lingering senescent cells accumulate with age, and secrete a mix of damaging signal molecules that produce chronic inflammation, damage tissue structure, and alter the behavior of nearby cells for the worse. This is known as the senescence-associated secretory phenotype (SASP), and PAI-1 is involved in both the SASP and in some of the processes by which cells become senescent. Studies show that inhibition or loss of PAI-1 reduces some of the harms now known to be associated with senescent cell presence, and in doing so slows measures of aging.

There is all sorts of past research into PAI-1 and senescent cells that we might choose to draw lines between. To pick one example, PAI-1 inhibition can slow atherosclerosis, just as can removal of senescent foam cells in atherosclerotic plaque. There are no doubt overlapping mechanisms here, though it seems clear that reducing PAI-1 levels has a variety of other effects as well. Those effects can't be all that terrible given the existence of a lineage of thriving human mutants lacking PAI-1, something that is always a good demonstration to have in hand. There are a few other beneficial mutations with a small human population to examine, such as those related to reduced blood lipids or myostatin loss of function; we may see many of these lines of research result in therapies in the years ahead.

And yet! While there will no doubt be an avalanche of funding into bringing PAI-1 inhibitors to the clinic, ask yourself this: if tinkering with a fraction of the harmful secretions of senescent cells is this beneficial, how much better will it be to remove these damaging cells entirely via senolytic therapies? All of those involved in this field should spend more time than they do on work with a higher expectation value, I believe.

The burden of aging falls most heavily on the poor, though it has to be said that the differences between rich and poor are small in comparison to the absolute degree of harm done by aging.

It has been a disappointment to see the Gates Foundation near entirely bypass this area of research up to fairly recently, presumably because they do hold this strange view of aging being either a non-issue, or a problem of wealthy regions.

From a utilitarian perspective, nothing that goes on in the poorest parts of the world rises to the level of harm done by age-related disease. Not even close.

There is a fair amount of more recent research in support of a microbial contribution to Alzheimers, and rather than just mediating through inflammation, disrupting metabolism in ways that accelerate amyloid deposition. I believe this ties more closely with research into vascular amyloid, if you look at who is involved, which may be why you haven't encountered it.

You might see https://doi.org/10.3389/fnagi.2017.00336 as a sample review paper that talks about oral bacteria that are capable of spurring amyloid formation in addition to spirochetes.

Lastly one of the complaints I've heard from someone involved in the cerebrospinal fluid drainage side of Alzheimer's research is that it is really, really hard to fight the amyloid clearance by immunotherapy dominant faction to get any funding or attention for alternatives. They just don't want to hear it.

Another point is that a majority of Alzheimer's patients have other neurodegenerative conditions, with vascular dementia being one of the most common. So it is reasonable to expect that you can in fact meaningfully address Alzheimer's and see little to no improvement in a patient.

The slow pace of progress towards clearance of amyloid, in that only in the past year has one of the immunotherapy trials actually looked promising, has provoked a lot of alternative theorizing these past five years. Some it is clearly not so great, such as the fellow who argues that it is caused by rising use of paracetamol (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921468/ ), but some lines of theory are much more compelling. A more encompassing synthesis is emerging in which microbial infection by spirochetes and gum disease bacteria (e.g. see https://doi.org/10.3389/fnagi.2017.00336 ) that can provoke amyloid formation as well as failing drainage of cerebrospinal fluid (e.g. see https://doi.org/10.1002/ana.24271, https://www.ethz.ch/en/news-and-events/eth-news/news/2017/11..., etc) that stops removal of amyloid, tau, etc are as important as purely cell focused considerations of the biochemistry of amyloid beta.

For an example of the new type of venture emerging now as a result of all of this you might look at Leucadia Therapeutics, working on a way to restore drainage through the cribiform plate, but there will be more in the years ahead to complement the immunotherapy for amyloid and tau mainstream.

Kurzweil's schedule is unrealistic, but his basic outline of how the job gets done is an accurate portrayal of one path ahead to physical immortality.

I wrote this a few years back:

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There exist a growing number of people propagating various forms of the viewpoint that we middle-aged folk in developed countries may (or might, or certainly will) live to see the development and widespread availability of radical life extension therapies. Which is to say medical technologies capable of greatly extending healthy human life span, probably introduced in stages, each stage effective enough to grant additional healthy years in which to await the next breakthrough. You might think of Ray Kurzweil and Aubrey de Grey, both of whom have written good books to encapsulate their messages, and so forth.

Some people take the view of radical life extension within our lifetimes at face value, whilst others dismiss it out of hand. Both of these are rational approaches to selective ignorance in the face of all science-based predictions. It usually doesn't much matter what your opinion is on one article of science or another, and taking the time to validate science-based statements usually adds no economic value to your immediate future. It required several years of following research and investigating the background for me to feel comfortable reaching my own conclusions on the matter of engineered longevity, for example. Clearly some science-based predictions are enormously valuable and transformative, but you would lose a lifetime wading through the swamp of uselessness and irrelevance to find the few gemstones hidden therein.

As a further incentive to avoid swamp-wading, it is generally well known that futurist predictions of any sort have a horrible track record. Ignoring all futurism isn't a bad attention management strategy for someone who is largely removed from any activity (such as issuing insurance) that depends on being right in predicting trends and events. You might be familiar with the Maes-Garreau Law, which notes one of the incentives operating on futurists: 'The Maes-Garreau Law is the statement that "most favorable predictions about future technology will fall within the Maes-Garreau Point", defined as "the latest possible date a prediction can come true and still remain in the lifetime of the person making it".'

If you want to be a popular futurist, telling people what they want to hear is a good start. "You're not going to be alive to see this, but..." isn't a compelling opening line in any pitch. You'll also be more convincing if your yourself have good reason to believe in your message. Needless to say, these two items have no necessary relationship to a good prediction, accuracy in materials used to support the prediction, or whether what is predicted actually comes to pass. These incentives do not make cranks of all futurists - but they are something one has to be aware of. Equally, we have to be aware of our own desire to hear what we want to hear. That is especially true in the case of predictions for future biotechnology and enhanced human longevity; we'd all like to find out that the mighty white-coated scientists will in fact rescue us from aging to death. But the laws of physics, the progression of human societies, and advance of technological prowess don't care about what we want to hear, nor what the futurists say.

I put value on what Kurzweil and de Grey have to say about the potential future of increased human longevity - the future we'll have to work to bring into being - because I have performed the due diligence, the background reading, the digging into the science. I'll criticize the pieces of the message I don't like so much (the timescale and supplements in the case of Kurzweil, WILT in the case of de Grey), but generally I'm on board with their vision of the future because the science and other evidence looks solid.

But few people in the world feel strongly enough about this topic to do what I have done. I certainly don't feel strongly enough about many other allegedly important topics in life to have done a tenth as much work to validate what I choose to believe in those cases. How should one best organize selective ignorance in fields one does care about, or that are generally acknowledged to be important? What if you feel - correctly, in my humble opinion - that engineered longevity is very important, but you cannot devote the time to validate the visions of Kurzweil, de Grey, or other advocates of longevity science?

The short answer is trust networks: find and listen to people like me who have taken the time to dig into the background and form our own opinions. Figuring out whether ten or twenty people who discuss de Grey's view of engineered human longevity are collectively on the level is not too challenging, and doesn't require a great deal of time. We humans are good at forming accurate opinions as to whether specific individuals are idiots or trustworthy, full of it or talking sense. Fundamentally, this establishment of a trust network is one of the primary purposes of advocacy in any field of endeavor. The greater the number and diversity of advocates to have taken the time to go digging and come back to say "this is the real deal," the more likely it is that that they are right. It's easy, and probably good sense, to write off any one person's views. If twenty very different people are saying much the same thing, having independently come to the same viewpoint - well, that is worth spending more time on.

One of the things I think we need to see happen before the next decade is out is the establishment of more high-profile longevity advocates who discuss advancing science in the Kurzweil or de Grey vein: nanotechnology, repairing the molecular damage of aging, and so on. Two, or three, or five such people is too few.

"Healthy aging" and "successful aging" as they are used in the research community are fig leaves to avoid talking about extension of human life. The researcher pretends that ways to remove or slow aspects of aging will not in fact extend the operating life span of the biological machinery making up a human individual.

It is a form of institutional cowardice in most cases, not a belief that we can magically engineer humans that live in excellent health and then somehow drop dead on the present schedule. Drop dead of what, if health is excellent, if age-related disease is prevented, if declines do not exist any more?

We are machines, complex yes, but subject to exactly the same statistical laws governing the operation of any system. See reliability theory and its application to, separately, electrical engineering and biological aging, for example.

A better argument against this line of development is that it is demonstrably expensive and low-yield.

There are far better R&D approaches to maintaining health over the course of aging, but they get a tiny fraction of the effort lavished on exercise and calorie restriction mimetics, despite the continued absence of concrete therapeutic outcomes resulting from all of that investment.

The reason for this is probably that exercise and calorie restriction mimetic research dovetails well with the real underlying scientific goal of mapping metabolism, where as better approaches tend to bypass this need for mapping, focusing instead on well-known forms of damage that cause age-related decline.

Some papers showing direct connections between senescent cells and specific aspects of aging, in many cases turning back that aspect by removing the senescent cells.

Osteoporosis: https://doi.org/10.1038/nm.4385

Fatty liver disease: https://doi.org/10.1038/ncomms15691

Disruption of platelet formation: https://doi.org/10.3389/fonc.2017.00188

Osteoarthritis: https://dx.doi.org/10.1038/nm.4324

Disruption of regeneration: https://doi.org/10.3389/fcell.2017.00049

Lung fibrosis: https://doi.org/10.1183/13993003.02367-2016

Pulmonary function in general, including tissue elasticity: https://doi.org/10.1172/jci.insight.87732

Atherosclerosis: http://dx.doi.org/10.1126/science.aaf6659

Vascular calcification: http://dx.doi.org/10.18632/aging.101191

Chronic kidney disease: https://doi.org/10.18632/oncotarget.17327

Cardiac hypertrophy: https://doi.org/10.1371/journal.pone.0182668

Cardiac fibrosis and function in general: https://doi.org/10.1093/eurheartj/ehx454

This is largely a promo for Unity Biotechnology and the associated labs. It fails to mention, e.g. SIWA Therapeutics and their work on antibodies, Oisin Biotechnologies and their gene therapy DNA constructs for destroying cells based on internal chemistry, the company that David Sinclair is starting for senolytics, that Betterhumans has beaten Unity to the punch and is currently running phase 0 human pilots of dasatinib and quercetin on a non-profit basis. Also that senescent cell clearance didn't magically spring into being in 2011, but appears clearly in Aubrey de Grey's position paper on human rejuvenation in 2002, and the Methuselah Foundation, SENS Research Foundation, and others have been advocating hard for more work in this direction in the face of a research community that rejected it for a decade.

But hey, if you beat the competitors to be the first to raise 9-figure sums of venture capital, then you too can engineer attention to shine on you only, and rewrite history more or less as you like for a while.

So far all ways to address aging in mice have slowed aging by tinkering with metabolism, but slowing down the damage accumulation. They all produce much larger effects in short-lived species, probably because long-lived species have evolved to have many of these metabolic items turned on already. Calorie restriction extends life by 40% in mice, and I can assure you that while it is pretty beneficial in humans, you are not going to add more than a couple of extra years. Senescent cell clearance is the first way to address aging that involves repair of damage rather than slowing it down: we have no idea how the size of benefit in mice will translate to humans. So 25% gains in mice can be exciting here, whereas for any slowing-aging-only approach it would be a yawn.

This should probably be considered an anti-inflammatory therapy rather than an anti-aging therapy. Inflammation is a sufficiently sizable driver of frailty syndrome to make that beneficial, but this is not addressing root causes, just compensating a little for one of the secondary consequences.

The scope of the possible in the near term is to find way to incrementally improve the condition, not produce a sizable reversal, but that is an improvement over the current situation, given that there is no effective treatment. The closest thing to a standardized, proven, reliable class of stem cell therapies involves the use of mesenchymal stem cells, sourced from a patient, or from lines of cells grown and engineered for transplantation with minimal risk. The primary outcome of mesenchymal stem cell therapies, or at least the reliable outcome, is a reduction in the systemic, chronic inflammation that accompanies old age. While it is entirely possible that other mechanisms are at work, the cells typically don't last long following transplantation, and thus it is the brief signaling changes that must produce benefits that can last for months or longer.

Chronic inflammation is a major problem in aging. It drives progression of most of the age-related conditions, and high levels of inflammation are certainly considered to be a major component of frailty syndrome in the old. In the context of a general treatment for frailty based on reductions in inflammation, the focus is less on the acceleration of specific age-related conditions over time, however, and more on the immediate consequences of constant high levels of inflammation for cell biochemistry, pain, cognitive function, joint function, regeneration, and tissue maintenance. Many aspects of age-related dysfunction are to some degree being actively maintained in their current impacted state by the presence of inflammation - take away that inflammation, and the problems subside a little, back to the lower level of harm and loss expected due to accumulated cell and tissue damage.

In recent years, it has become clear that chronic inflammation, as opposed to the normal short-term inflammation resulting from injury or infection, disrupts the finely tuned dance carried out between tissue and immune system needed for regeneration. This is an emerging theme in the investigation of how senescent cells cause aging, for example, as these unwanted cells are potent sources of inflammatory signaling. So if we see unreliable or marginal benefits from stem cell therapies that look like enhanced regeneration, it might well be that this is at root a short-term reduction in the age-related disruption of tissue maintenance - perhaps enough to allow a little reconstruction to take place in some patients. This is speculation, of course, and the cellular biochemistry is challenging to investigate; we should probably expect a first generation of moderately reliable therapies in advance of complete understanding of their mechanisms. Here is another point to consider on this topic: if the inflammation model of benefits is correct, then clearance of senescent cells should be at least as good a treatment for frailty as mesenchymal stem cell transplant, and probably better and more lasting.

This is an example of the strange idea that there is "normal aging" that is fine because it is normal and is somehow completely different from whatever parts of aging that we call age-related disease and have decided are not "normal aging". Semantics, all of it.

All of this is "normal aging". Dementia is "normal aging." Normal aging is terrible and creates a varying distribution of disease states in people. Those disease states are the end of a random walk of primary aging (i.e. unavoidable molecular damage caused by the normal operation of metabolism) and secondary aging (i.e. being fat, smoking, etc, things that add extra molecular damage or extra consequences that are similar to the consequences of the unavoidable molecular damage), and everyone ends up somewhere different in that state space. All completely normal.

The only way to prevent and cure the parts of normal aging that we have defined to be age-related disease is to fix the causes of aging, because age-related diseases ARE aging. It is all the consequence of exactly the same processes at root. The three current views of what those causes are:

SENS: http://www.sens.org/research/introduction-to-sens-research

Hallmarks of Aging: http://dx.doi.org/10.1016/j.cell.2013.05.039

Seven Pillars: http://buckinstitute.org/CellCommentary

I finally signed up in 2016 as well. It is The Responsible Backup Plan in the grand scheme of things, assuming you are someone who likes to be alive. Around that time I set down some high level notes on what I think to be important in the process, which can be found here:

https://www.fightaging.org/archives/2016/07/finally-signed-u...

https://www.fightaging.org/archives/2016/05/overfund-the-lif...

"I have put off signing up for cryopreservation for a decade or so. This isn't uncommon; after all, it involves paperwork, adult responsibility, planning ahead, thinking about unpleasant events, and all that. People put off many other things for these and similar reasons. Writing wills, buying houses, getting married, starting companies, and so on. That doleful feeling of some unknown scope of paperwork that will have to be accomplished in the event that you do get your act together and set forth to be a responsible adult is ever a strong deterrent. Still, sooner or later all these tasks have to be carried out, and while no-one enjoys wading through legal documents, it is never as bad as you think it is going to be. If you are unfamiliar with the process of signing up for cryonics organization membership and cryopreservation, let me tell you that it is much less work than buying a house. It is about two and half times the work of getting a life insurance policy, if that helps calibrate things any better."

I want a lab that can also provide pilot phase 0 trial organisation infrastructure - or equivalent in another jurisdiction - as a product. I need a lab for lab stuff. That is easy. It is a crowded field. What is annoying and costly and time consuming is the legal and logistical setup for animal and especially initial human trials. A one stop shop would be very useful.

Evolution doesn't optimize for benefits to the individual. If it did, we'd all regenerate like salamanders.

That any sort of cell therapy or signaling change works at all to improve health is indicative that the standard issue biochemistry in mammals is suboptimal.

The risk from this sort of thing, like all efforts to change cell behavior towards greater tissue maintenance, is cancer. One of the most interesting aspects of the whole field of regenerative medicine is the degree to which cancer hasn't emerged, however. There seems to be considerable leeway for crude methods to improve regeneration to work without large increases in cancer risk.

Damien Broderick, given his related non-fiction on the singularity and other topics.

https://en.wikipedia.org/wiki/Damien_Broderick

The article focuses on inherited diseases, but that is a proving ground for the later, larger market of enhancement. An order of magnitude more healthy people will be willing to undergo gene therapy to gain greater muscle mass and less fat tissue (myostatin / follistatin) or greater stem cell activity (telomerase) than is the case for patients with serious inherited conditions willing to undergo gene therapy.

The breakthrough waiting to take place is the development of a methodology of reliable transfection of large enough number of cells to produce the desired outcome in adults. That seems to be not that far away, but it isn't the case today; the gene delivery mechanisms work, but that isn't the same thing as succeeding in altering a sufficient number of cells every time.

This is one of the reasons why there are no clinics offering enhancement gene therapies via medical tourism. That will happen soon, however, in a similar pattern to that followed for stem cell therapies at the outset of their clinical availability.

There is a general cure for cancer.

Look up interdiction of telomere lengthening. Different groups are looking into how to sabotage telomerase and ALT mechanisms. If both can be achieved, then any cancer can be shut down. Those are the only ways to lengthen telomeres, and cancers cannot live without them.

Finding an ALT drug candidate is as simple as running assays on the drug libraries; the assay hasn't existed for long, which is why this hasn't been done yet in any major way. The SENS Research Foundation raised $70k last year to run a preliminary scan of a few thousand compounds. That's about what it costs these days.

So not quite garage science yet, but getting close.

The killer application for gene therapy is enhancement, not disease treatment. Genetic diseases are present in only a tiny number of people, and so the markets that will form there will be miniscule in comparison to those that improve healthy people.

This will play out over the next decade or two.

Look at, e.g. gene therapy for inherited disorders (lysosomal storage diseases, DNA repair deficiencies, etc, etc) versus myostatin / follistatin gene therapy that increases muscle mass, reduces fat tissue, and generally adjusts metabolism into a better direction.

The first companies to commercialize the former will be successful mid-sized biotech concerns. The first companies to commercialize the latter will be behemoths.

The state of development in this field is dependent on methods of delivering genes that are reliable, tissue specific, and achieve high degrees of cell coverage. Once that happens, which seems fairly close at hand, then we'll see a very interesting expansion of the medical tourism marketplace into enhancement technologies, a market hundreds of times as large as therapies for sick people.

The aim is to see whether or not this can usefully change the balance of signaling molecules to, say, spur greater stem cell activity. There has been a trial in Alzheimer's patients, but some signs in animal studies that transfusions from young to old don't do much. It seems useful to speed up the process of determining whether or not transfusions are an interesting line of research, or something that only looked promising. That means more patients and larger trial populations, which Ambrosia is working on.

These transfusion initiatives are one of a number of outgrowths of parabiosis research in mice. Heterochronic parabiosis is the name given to connecting the circulatory systems of an old and a young individual. The older mouse shows a modest rejuvenation in a number of measures of aging, and the younger mouse shows some greater signs of aging - though most of the focus here has been on the old mouse. In recent years this technique has been used to search for potentially actionable differences in levels of specific signal molecules circulating in the bloodstream. For example, stem cell activity declines with aging, and this is likely governed by signaling processes. If levels of the most relevant molecules could be adjusted in old individuals, it might be possible to produce benefits that look quite similar to those of stem cell therapies: increased regeneration and tissue maintenance. This class of approach puts damaged, aged cells back to work, and does little to address causes of aging based on accumulation of metabolic waste, such as cross-links that stiffen blood vessels, but to the degree that it can improve health it is probably worthy of further investigation in the same way as stem cell therapy was back in the day.

One potential shortcut to the production of therapies is to perform transfusions: deliver young blood or young plasma to old individuals. I call this a potential shortcut because it really is still very uncertain as to (a) whether or not the whole process works in humans anywhere near as well as it works in mice, and (b) whether or not transfusions will recapture the effects of parabiosis to a useful degree. The evidence in mice suggests so far that it may not. It is possible to paint all sorts of scenarios in which the fact that old and young cells are in contact, feeding signals to one another in a feedback loop, is necessary to produce beneficial changes in the old individual. It is also possible to imagine signals with a short half-life, that won't be recaptured in transfusions, or changes in the old environment that are based on an increased level of specific signal molecules. That increased level won't be changed in the slightest by the arrival of some amount of young blood plasma. Only reduced levels are likely to be impacted that way.

In any case, testing and perhaps ruling out the fast path of transfusions seems like a fair plan. If it works, it will draw in more funding to build the better option of manipulating signal molecule levels directly. It if doesn't work, that result will direct scientists to focus on more productive lines of research and development. There is some grumbling from the expected quarters over the structuring of this present initiative by Ambrosia, but getting it done is better than not getting it done. The data will be useful in the sense that only sizable effects are interesting, and thus before and after data for participants will be convincing. Marginal effects, of the sort in which it would have been useful to have a control group to establish whether or not any benefits actually resulted, would mean that this probably isn't worth further exploration. Still, this well demonstrates the fact that many scientists who work within the heavily regulated, slow, and repressive system of medical development really don't like it when people try to get things done more rapidly and more inventively. To the extent that it closes down productive avenues, this is a dangerous attitude.

Recent commentary suggests that none of the results so far are either large enough or extensive enough to definitively be something other than the placebo effect, chance, or other items such as a patient making lifestyle changes. I think there is some skepticism regarding the potential effectiveness of transfusions of young blood in any case; the data is somewhat mixed, and underlying theory on what is going on still in flux. Recent research suggests that the effects observed in parabiosis studies of mice with joined circulatory systems are due to a dilution of harmful factors in old blood rather than a delivery of helpful factors from young blood, for example. If the case, that would mean that transfusions should produce very limited results at best. Still, obtaining data is the important thing, and that is what is being done here. Those complaining the loudest should put in the work to raise funds and run a study they way they would prefer to.

And further, whenever anyone turns up to say "metformin is great", just point them at the studies showing that aspirin does a fair job of extending healthy life span in a variety of laboratory species. Arguably the aspirin life span studies show more consistent results than metformin, though there are fewer of them. And we all know what aspirin does for human life span.

For senolytic therapies, look at Unity Biotechnology's pharmaceutical trials starting this year, Oisin Biotechnologies' gene therapy approach, SIWA Therapeutics with an antibody approach. There are a dozen or so candidate drugs worth looking at, in addition to the non-drug approaches.

If you have the connections you can order any of the various senolytic pharmaceuticals today and try them. Though this would be unwise for the chemotherapeutics with animal data, since they are not friendly compounds, and worth waiting for a year or two to see how more targeted things like FOXO4-DRI work out in human tests. A year or two from now will be a great time for self-experimentation on this front, given the range of candidates and the size of the effects in mice where there is data. Today the situation is in an awkward state where some of the easier pharmaceuticals to handle are either going to have tiny effects or have no animal data, while the others still need human data. Still, I would expect medical tourism to flourish for these things quite soon: the drugs are cheap, the beneficial effects sizable.

The results for metformin in animal studies are all over the map, with many studies showing no results on life span or health span. A great many people have taken metformin for a long time with no great and obvious results. Short-lived species have far more plastic life spans in response to metabolic adjustment in comparison to humans; the two most reliable and sizable effects on mice (growth hormone receptor knockout and calorie restriction) do not have similarly sizable effects in humans. Laron syndrome sufferers and calorie restriction practitioners do not live significantly longer than others.

The one and only reason why metformin is getting into trials is as a political lever to get the FDA to acknowledge aging as a medical condition with defined causes for which treatments will be approved. Metformin couldn't really be rejected in the way the FDA likes to reject a lot of things because it is so widely used and has been so widely used for a long time.

The future of human longevity is not tinkering with metabolism to try to push it to be a little more like calorie restricted metabolism. That is a waste of time and effort. It is enormously expensive to carry out the work to try to understand metabolism well enough to adjust it safely. Hell, look at the past 20 years of work on calorie restriction: how much has been spent, how many man-years focused on it, and the research community is still only scratching the surface on how to induce similar effects via therapies.

Yet there is another approach, one that is far more cost-effective in time and money. Repair the causes of aging. Look at removal of senescent cells: in a bare few years, and at far less cost than has been spent on calorie restriction mimetic development, researchers have demonstrated robust effects and reversal of numerous age-related conditions in mice. Unlike metformin and similar drugs, the results are consistent, sizable, and produce rejuvenation in old individuals, not just a slight slowing of aging.

There is an enormous difference between the bad way forward (typified by metformin) and the good way forward (typified by senolytics). In the former we all die on the same schedule as our parents and grandparents. In the latter we can gain decades or more of additional healthy life.

Progress in cell therapy strongly depends on progress in controlling cell state. A world in which the research community has advanced enough to make stored cells really useful, but not advanced to the point at which it couldn't just recreate something very similar to those cells from an aged skin sample at little cost seems highly unlikely.

Mutations are stochastic.

Pick a hundred cell lineages from skin samples, and merge back to the common root genome minus the stochastic mutations in their ancestors. Then apply CRISPR or some selection technique to the skin sample you've converted to iPSCs to obtain the genome you want. Most of that could be done with today's technology, were anyone so inclined.

Twenty years from now this will be an afternoon intro project on one of the lab machines in CellBio 101.

Banking cells for the purpose of use later in regenerative medicine is supremely pointless. It is a hedge against technological development in cell reprogramming and repair - technological development that is progressing at a revolutionary pace right now, and that will soon enough enable old cells to be restored to youthful configurations. Merely reprogramming cell samples into induced pluripotent stem cells has already been shown to do some of that.

Let us say for the sake of argument, however, that the hedge turns out to be worthwhile, and the exceedingly unlikely course of biotechnology not progressing much past where it is now over the next 20 years takes place. Woe. But then having those banked cells is basically useless because there is very little of worth you can do with them. All of the potential cell therapy applications that might be rolled out today are marginal for someone at very late age.

So cell banking for future use in cell therapies is basically a business that is only useful to its customers if the biotechnology of cellular control both fails to advance and advances spectacularly.